R43 SBIR: Development of an iPSC-derived human vascular system for drug development. ABSTRACT Human inducible pluripotent stem cells (iPSCs) can be differentiated into vascular endothelial (iEC) and smooth muscle (iSMC) cells and hold immense potential for developing drugs in genetically defined subpopulations and for patients with vascular rare diseases, such as Marfan's syndrome, from which iPSCs can be acquired. However, it has not been clearly demonstrated that iECs and iSMCs are phenotypically similar to differentiated human primary adult vascular cells, including disease risk factor and drug responsiveness. This cannot be understated as recent studies with iPSC-derived hepatocytes have shown that these cells provide limited utility to the FDA and pharmaceutical industry for drug discovery as they retain many fetal-like characteristics, failin to express primary hepatocyte levels of many cytochrome p450 enzymes, including the CYP3A family, which is responsible for metabolizing over 60% of drugs in humans. HemoShear, LLC is a biotechnology research company that utilizes patented methodologies (US 7,811,782) to restore in vivo biology to human primary cells in co-culture in vitro. In this system, vascular cels are rescued from a non-physiological state as indicated by restoration of region-specific in vivo morphology, expression of mature differentiation markers and function. Importantly, cells respond to drugs and disease, thrombotic and inflammatory risk factors that approximate in vivo human exposure levels, which are often 1 to 2 orders of magnitude different from standard 2D static systems. The purpose of this SBIR is to determine whether iECs and iSMCs in the HemoShear Vascular system achieve in vivo-like responsiveness similar to human primary vascular cells for utility in safety and drug discovery development, creating the framework for a much needed platform for drug development in genetically defined vascular diseases.